Nanoparticles are engineered structures with dimension of 100 nanometers or smaller. Available evidence indicates that the properties of nanoparticles may substantially differ from the same composition in the micrometer scale. However, the biological effects of nanoparticle exposure are little known yet. Our preliminary results show that exposure of epithelial cells to tungsten carbide cobalt (WC-Co) nanoparticles produced high levels of reactive oxygen species (ROS). WC-Co nanoparticles induced AKT and ERK1/2 activation, and increased the transcriptional activation of AP-1, NF-kappaB, and VEGF. We hypothesize that WC-Co nanoparticles induce angiogenesis through ROS signaling, which in turn regulates PI3K, AKT and ERK1/2 activities. To test this hypothesis, we will perform the following four aims. In Aim 1, we will identify which species of ROS are induced in lung epithelial cells exposed to the nanoparticls and the mechanism of ROS generation in the cells. Aim 2 will determine what signaling pathways and molecules are regulated by the nanoparticles, and whether they are mediated through ROS in the cells. Aim 3 will determine the effects of the nanoparticles in lung epithelial cells for inducing angiogenesis, and roles of ROS and signaling molecules in nanoparticle-inducing angiogenesis. Aim 4 will use mouse model and transgenic mice to further study the roles and mechanism of WC-Co nanoparticles in regulating signaling pathways and angiogenesis. This proposed work will provide the roles and mechanism of the nanoparticles in angiogenesis and other biological effects, and identify specific ROS-mediated signaling molecules for regulating angiogenesis. After we learn the biological responses of the nanoparticles and the underlined mechanism, we will be able to develop mechanism-based interventions, such as specific antioxidants, to decrease toxicity of WC-Co nanoparticles and other nanoparticles in the future. Nanoparticles are engineered structures with dimension of 100 nanometers or smaller. However, the biological effects of nanoparticle exposure are little known yet. In this study, we plan to study the biological effects of WC-Co nanoparticles by determining the roles and mechanism of the nanoparticles in inducing ROS production, PI3K, AKT, and ERK activation in human lung epithelial cells, and to study the effects of the nanoparticles in inducing angiogenesis. This proposed work will provide the roles and mechanism of the nanoparticles in inducing angiogenesis and other biological effects. This information is also useful for us to develop mechanism-based interventions, such as specific antioxidants, to decrease toxicity of WC-Co nanoparticles and other nanoparticles in the future.